Summary

In the total population, stroke is the fifth most common cause of death and the leading neurological cause of long-term disability in the United States, accounting in 2011 for $34 billion in health care costs. With the advent of sensitive brain imaging techniques, it is common to observe magnetic resonance imaging evidence of subclinical vascular brain injury, such as covert brain infarcts (CBI) and white matter hyperintensities (WMH). In an unselected sample of persons age >65 years without a history of clinical events, 10%–15% had CBI and 95% had WMH. The subclinical findings do not cause abrupt clinical symptoms but are often associated with cognitive decline and with an increased risk of subsequent stroke. Therefore, the clinical and public health burden of cerebrovascular disease is far greater than that of overt clinical disease. This burden is higher in persons with diabetes. Diabetes, a risk equivalent for cardiovascular disease, has been recognized as one of the major risk factors for stroke and subclinical vascular brain injury, such as CBI, WMH, and vascular cognitive impairment.

Stroke is clinically defined as an acute-onset focal neurological deficit persisting for more than 24 hours. About 85% of all strokes are ischemic, and the other 15% are hemorrhagic. Ischemic stroke is caused by an abrupt blockage of the artery, either by an embolus from the heart or from a more proximal artery, or from an in situ thrombus growing to occlude a cerebral artery affected by an atherosclerotic plaque, leading to an acute blockage of blood supply to the brain. Hemorrhagic stroke can result in accumulation of blood in the substrate of the brain, which is called intracerebral hemorrhage, in the cerebrospinal fluid around the brain, or in the cerebrospinal fluid spaces within the brain.

The etiology of stroke in persons with diabetes is comparable to the etiologies in other populations. However, multiple underlying pathophysiological processes in diabetes lead to a high prevalence of small vessel and/or large vessel atherosclerosis in persons with diabetes. Persons with diabetes have about twice the risk for stroke, particularly of ischemic stroke. Diabetic individuals after stroke have about a 25% reduction in a favorable outcome, such as being able to function independently in activities of daily living, and are more likely to die from the stroke. Those who survive are more likely to have recurrent strokes and to develop vascular cognitive impairment than persons without diabetes.

Diabetes is more common in nonwhite populations, and stroke risk has been assessed in various racial/ethnic subgroups. Diabetes is at least as important a risk factor for stroke in blacks, Japanese Americans, and Native Americans as it is in whites, with a 40%–100% higher risk in racial/ethnic minorities.

Coexistence of various risk factors, such as hypertension and hyperlipidemia, and concomitant coronary or peripheral vascular disease are common problems in persons with type 2 diabetes and are also independent risk factors for stroke and its serious complications. Impaired glucose tolerance and the metabolic syndrome, as well as microalbuminuria, are other stroke risk factors in persons with diabetes, with the metabolic syndrome increasing risk by 20%–40% and microalbuminuria increasing risk by approximately 80%.

Strict control of hyperglycemia has not been shown to reduce stroke incidence in persons with diabetes. Vigorous management of primary disease (diabetes) and careful identification and treatment of the concomitant vascular risk factors, especially hypertension, along with lifestyle modifications remain the fundamental approach for stroke prevention in this vulnerable population. Statins and low-dose aspirin may also be beneficial in preventing stroke or attenuating its adverse impact. Studies of oral hypoglycemic drugs and peroxisome proliferator-activated receptor-gamma (PPAR-γ) inhibitors have not, so far, shown a convincing effect on altering stroke risk among persons with diabetes.

Introduction

In the total population, stroke is the fifth most common cause of death and the leading neurological cause of long-term disability in the United States, accounting in 2011 for $34 billion in health care costs; the mean lifetime cost to care for a single patient with an ischemic stroke was estimated at $140,048 (1). In 2014, there were an estimated 795,000 strokes, approximately 610,000 being new or incident strokes and around 185,000 being recurrent strokes (1).

Persons with diabetes have about twice the risk for stroke compared to those without diabetes, particularly for ischemic stroke. Yet, the etiology of stroke in persons with diabetes is comparable to etiologies in nondiabetic populations. Multiple underlying pathophysiological processes in diabetes, however, lead to a high prevalence of small vessel and/or large vessel atherosclerosis in individuals with diabetes.

This chapter describes the measurement and classification of stroke and stroke subtypes, and in persons with diabetes, the pathophysiology of stroke, the epidemiology of stroke, predictors of stroke risk, control of risk factors for stroke, and the disease course and prognosis after a stroke.

Description, Measurements, and Classification of Stroke in Diabetes

Definitions, Measurements, and Classifications

Traditionally, stroke is defined as an acute-onset focal neurological deficit persisting for more than 24 hours. Ischemic stroke (due to insufficient blood supply to a portion of the brain) accounts for approximately 85% of all strokes, and the other 15% are of hemorrhagic type (Figure 19.1) (2,3). Ischemic strokes are classified further based on presumed etiology; a commonly utilized classification of stroke subtypes is the TOAST classification, named for the Trial of Org 10172 in Acute Stroke Treatment, the clinical trial in which this system was initially developed (3). An alternative, more automated system used in genetic analyses is the Causative Classification of Stroke System (4). In these classification systems, ischemic strokes are subdivided into five categories as being due to: (1) large artery atherosclerosis, (2) cardioembolism, (3) small artery occlusion (or lacunar strokes), (4) stroke of other determined etiology, and (5) stroke of undetermined etiology. Hemorrhagic strokes are categorized as subarachnoid or intracerebral hemorrhages. Subarachnoid hemorrhages are due to rupture of an aneurysm, typically in the large intracranial arteries, into the subarachnoid space. Intracerebral hemorrhages are further categorized as lobar (in the cerebral hemispheres) or deep (in the basal ganglia, thalami, brainstem, or cerebellum).

A transient ischemic attack (TIA) is a brief episode of neurologic dysfunction lasting <24 hours, resulting from focal but transient brain ischemia without acute infarction on brain imaging. TIA is a risk factor for sub sequent stroke. The 90-day risk of stroke after a TIA is as high as 17%, with the greatest risk apparent in the first week. Whereas the common clinical definitions of stroke and TIA are based on the clinical presentation, a diagnosis of stroke and TIA can be confirmed with brain imaging techniques. Non-contrast computed tomography (CT) detects most hemorrhagic and some ischemic strokes, and brain magnetic resonance imaging (MRI) utilizes a sophisticated diffuse weighted imaging (DWI) technique for sensitive detection of acute ischemic brain injury in both TIAs and stroke (5).

FIGURE 19.1

Stroke Types.

Approximately 30%–50% of persons presenting with a TIA episode, with clinical symptoms lasting <24 hours, have abnormalities on DWI suggesting acute brain infarction; thus, a new tissue-based TIA definition has been proposed to differentiate TIA episodes with and without positive imaging (6). Pending further study, the short- and long-term management of individuals with clinical TIA remains unchanged by whether or not they have concomitant MRI DWI abnormalities (5).

Covert brain infarcts (CBI) and white matter hyperintensities (WMH) are subclinical lesions identified only by brain imaging (CT or MRI) (5), and this has been an area of growing research interest, as the morbidity associated with these lesions is increasingly recognized (7,8).

This chapter focuses largely on clinical ischemic stroke in persons with diabetes. The frequency of hemorrhagic stroke in person with diabetes is the same as that in the general population (about 15%) (2,3,9), but this chapter does not consider hemorrhagic strokes in detail. Unless otherwise noted, diabetes refers to type 2 diabetes.

Pathophysiology of Stroke in Diabetes

Diabetes adversely affects the extracranial and intracranial arterial circulation, including small perforating vessels within deep brain structures. Several possible mechanisms underlying the acceleration of macrovascular and microvascular injury in persons with diabetes could contribute to the development of cerebrovascular disease (11). One postulated mechanism is that atherosclerosis is the result of the oxidative modification of low-density lipoproteins (LDLs) by reactive oxygen species (ROS), which triggers a cascade of atherosclerotic processes within the arterial wall. Diabetes itself increases the production of free ROS, which in turn is thought to promote endothelial dysfunction, arteriosclerosis/lipohyalinosis of penetrating end-arteries, and accelerated atherosclerosis of large arteries, explaining higher prevalence of small and large vessel disease stroke types among persons with diabetes. Additionally, hyperglycemia independently promotes proinflammatory processes, smooth muscle cell dysfunction, overproduction of growth factors, and activation of protein kinase C pathways, which may influence overall fibrinolytic capacities; all of these processes lead to an increased risk of thrombus formation, atherosclerosis progression, and plaque rupture (11). Diabetes is also an acknowledged risk factor for coronary heart disease, atrial fibrillation, and heart failure, each of which predisposes to cardioembolic stroke. Finally, diabetes is associated with increased rates of hypertension, which contributes to stroke risk.

Prolonged hyperglycemia may result in renal dysfunction. Microalbuminuria, an early clinical sign of diabetic nephropathy, is a risk marker for vascular disease in both persons with and without diabetes (12,13). When present at the time of diagnosis of type 2 diabetes, microalbuminuria may reflect the burden of underlying vascular risk factors and indicate the presence of cardiovascular disease (CVD) (14). If not effectively treated, microalbuminuria is followed by slowly progressive decline in renal function manifesting as macroalbuminuria or decreases in estimated glomerular filtration rate (eGFR) (15). A meta-analysis of 12 studies, with a total of 48,596 participants and 1,263 stroke events in an analysis adjusted for established cardiovascular risk factors, confirmed that presence of microalbuminuria was associated with greater stroke risk (relative risk [RR] 1.92, 95% confidence interval [CI] 1.61–2.28, p<0.001) (12). A similar trend was seen in studies (n=5) including only persons with type 2 diabetes (RR 1.70, 95% CI 1.43–2.04), but this did not reach statistical significance (p=0.26). However, the microalbuminuria definition was different in all five studies, including a urine albumin-to-creatinine ratio (UACR) of >2.5 mg/mmol (>22.1 mg/g) or ≥3.0 mg/mmol (≥26.5 mg/g) or a spot urine albumin concentration (UAC) of 150–299 mg/L (15–29.9 mg/dL) or 30–299 mg/L (3–29.9 mg/dL) (12). Among 1,181 stroke-free community subjects with type 2 diabetes, microalbuminuria was found to be an independent predictor of stroke (RR 1.83, 95% CI 1.16–2.87, p=0.09) (16). Another meta-analysis derived from 33 prospective studies, with more than 280,000 people, of whom 8,000 had stroke, demonstrated that persons with an eGFR <60 mL/min/1.73 m² had a 43% greater risk of having another stroke than persons with a normal baseline eGFR (RR 1.43, 95% CI 1.31–1.57, p<0.001) (17). This observation was true for persons with or without vascular risk factors, including diabetes, across all racial groups.

Over the course of the disease, a large number of persons with diabetes develop diabetic autonomic neuropathy (DAN), an independent risk factor for stroke (18). The underlying mechanisms by which autonomic nerve pathology contributes to the pathophysiology of stroke are largely unknown. Accelerated cerebral vascular damage and alterations in the regulation of cerebral blood flow in diabetic persons with DAN may increase the risk of stroke. Experimental studies demonstrate that stimulation of perivascular nitrergic nerves (cholinergic nerves releasing nitric oxide [NO]) may relax the cerebral arteries by the actions of NO and, thus, increase cortical blood flow. In DAN, nitrergic nerve degeneration may result in severe deficiency of NO and impaired vasodilation response to both nerve stimulation and shear stress in cerebral arteries, thus increasing susceptibility to strokes in diabetic rats (18,19).

Epidemiology of Stroke in Diabetes

The prevalence of self-reported stroke by age and sex in the general population based on data from the National Health and Nutrition Examination Surveys (NHANES) 2007–2010 is shown in Figure 19.2 (20). Prevalence was rare in young ages but rose to about 6%–7% in persons age 60–79 years and to about 14% in those age ≥80 years. Prevalence was similar by sex. Based on data from the Framingham Heart Study (FHS), however, women have a somewhat higher lifetime risk of stroke (20%–21%) compared to men (14%–17%) (21).

Incidence of first stroke in the general population is shown by race and year in Figure 19.3, based on data from the Greater Cincinnati/Northern Kentucky Stroke Study (GCNKSS) population (20). Incidence was 1.5–2 times higher in blacks than whites, regardless of type of stroke (ischemic, intracerebral hemorrhage, or subarachnoid hemorrhage), and was stable over time. The vast majority of stroke incidence was due to ischemia.

Prospective epidemiologic studies have confirmed diabetes to be an independent risk factor for ischemic stroke. The relative risk of stroke in persons with diabetes ranged from 1.8 to 6.0 (22). Whereas death rates among U.S. men and women with diabetes declined by almost 40% between 1997 and 2006 (23), the prevalence of diabetes actually increased, resulting in a parallel increase in the absolute number of vascular events in persons with diabetes (22).

Incidence and Prevalence of Stroke in Diabetes

Type 1 Diabetes

In the Pittsburgh Epidemiology of Diabetes Complications study, among 658 participants with childhood-onset type 1 diabetes followed for a mean duration of 15.4 years, 31 participants (mean age 40.2 years) experienced a stroke. Participants with stroke were older and had a longer duration of type 1 diabetes (mean duration 25 years) than persons without stroke. There was no difference in stroke risk based on sex or race. Participants who developed a stroke, either ischemic or hemorrhagic, were more likely to have albuminuria and to have a higher burden of concomitant vascular risk factors. Although the number of stroke events was small, the overall survival rates regardless of stroke type were 80.6%, 45.2%, and 9.6% at 1, 5, and 10 years, respectively, and were significantly worse after hemorrhagic than ischemic stroke (at 1 year, 95.2% vs. 50.0%, p=0.03) (24).

FIGURE 19.2

Prevalence of Stroke, by Age and Sex, U.S., 2007–2010.

FIGURE 19.3

Annual Age-Adjusted Incidence of First-Ever Stroke, by Race and Stroke Type, Greater Cincinnati/Northern Kentucky Stroke Study, 1993–1994, 1999, and 2005. Data represent hospital and out-of-hospital ascertainment. ICH, intracerebral hemorrhage; (more...)

Over a follow-up period of 6 years, approximately 3% of a cohort of African American persons with type 1 diabetes, assembled at discharge from hospital, developed a stroke (25). Significant limitations of this study were the hospital-based nature of the cohort and the lack of nondiabetic and white comparison groups (26). Prior studies in whites with type 1 diabetes demonstrated a 6% stroke incidence over a much longer follow-up period of 20 years, suggesting that the relative risk of stroke may be higher in blacks with type 1 diabetes.

The Nurses’ Health Study (NHS) evaluated the risk of stroke in women with type 1 or type 2 diabetes (26). The study utilized biennially mailed questionnaires to evaluate participants’ medical status. During 24 years of follow-up, 2,719 first strokes were reported among 116,316 participants. Participants were categorized as having type 1 diabetes if they were diagnosed with diabetes before age 30 years and reported use of insulin or a history of ketosis. All others were categorized as having type 2 diabetes. Over a period of 24 years, women with type 1 diabetes were six times more likely to have a stroke than those without diabetes. In comparison, those with type 2 diabetes had a twofold increase in stroke risk compared to women without diabetes. Limitations of this important analysis were the use of mailed questionnaires to establish interval history and the fact that less than three-fourths of all historical stroke events could be confirmed on record review. This study emphasizes the importance of distinguishing the type of diabetes when estimating the risk of stroke (26). However, the majority of studies evaluating the risk of stroke among populations with diabetes have involved only persons with type 2 diabetes.

Population Data on Stroke in Type 2 Diabetes

As illustrated in Table 19.1, National Health Interview Survey (NHIS) 2009–2010 data on self-reported stroke among adults age ≥55 years with and without diabetes were analyzed for Diabetes in America, 3rd edition. The prevalence of stroke in persons with diabetes was 11.6% compared to 5.1% in persons without diabetes and was higher in diabetic individuals across all subgroups. Regardless of diabetes status, prevalence was similar for women and men, highest for non-Hispanic blacks, and lowest for Hispanic groups and non-Hispanic Asians.

Diabetes in America analysis of data from the National Hospital Discharge Survey 2010 using International Classification of Diseases, Ninth Revision, codes for stroke (430–438) estimated that the prevalence of stroke (based on hospital discharges) among persons with diabetes (Table 19.2) was very similar to the NHIS estimates (based on self-reported stroke in persons with diabetes). For adults age ≥55 years who were hospitalized in 2010, the percentage of hospital discharges listing stroke among adults with diabetes was 10.1% compared to 8.4% in adults without diabetes. Because of the self-reporting of events and the substantial mortality associated with stroke, prevalence data may underestimate the burden of stroke in any sample.

TABLE 19.1

Prevalence of History of Stroke Among Adults Age ≥55 Years, by Diabetes Status, Age, Sex, and Race/Ethnicity, U.S., 2009–2010.

TABLE 19.2

Percent of Hospital Discharges Listing Stroke Among Adults Age ≥55 Years With and Without an Additional Diagnosis of Diabetes, by Age, Sex, and Race/Ethnicity, U.S., 2010.

Age and Sex Differences in Stroke Risk in Diabetes

Data collected during a 10-year follow-up period between the ninth and fourteenth biennial exams of the largely white FHS were used to compute sex-specific 10-year probabilities for risk of incident stroke. Computations were based on the levels of baseline vascular risk factors.

A 10-year stroke risk was estimated for adults age 55–84 years (Figure 19.4) (27), and the probability of stroke was provided for both men (Figure 19.5) and women (Figure 19.6), depending on level of risk factors (28). Among 5,734 participants (58% female, mean age 66 years), there were 472 stroke events, and approximately 8% of female and 11% of male participants with a diagnosis of diabetes developed stroke (28). The estimated probability of stroke increased in relation to an individual’s number of vascular risk factors, and the risk of stroke related to diabetes alone in both women and men was dramatic, with relative risks of 1.40 for women and 1.70 for men (28).

In the community of Rancho Bernardo, California, among 3,778 predominantly white men and women (age 50–79 years), 232 stroke cases occurred during a 12-year follow-up period. As in the Framingham cohort, the risk of stroke was higher among participants with diabetes compared to those without diabetes. In addition, the age-adjusted stroke mortality and morbidity rate among female participants with both diabetes and a concomitant diagnosis of hypertension (defined as >160 mmHg systolic or >90 mmHg diastolic) was nearly double the rate in women with diabetes alone (17.8% vs. 8.9%, p=0.02). This finding suggests that some of the increased risk of stroke among persons with diabetes is attributable to the increased prevalence of hypertension (29).

FIGURE 19.4

Estimated 10-Year Stroke Risk Among Adults Age 55–84 Years, by Sex and Risk Factors, Framingham Heart Study. Data are based on 472 stroke events occurring during 10 years of follow-up from biennial examinations 9 and 14. AF, atrial fibrillation; (more...)

FIGURE 19.5

Probability of Stroke in Men Age 55–84 Years and Free of Previous Stroke, Framingham Stroke Risk Estimator.

In the NHS, 116,177 women without CVD (age 30–55 years) were followed for 8 years. After adjusting for other known vascular risk factors, such as blood pressure and smoking, the relative risk of stroke among women with diabetes compared to women without diabetes was 3.0 (95% CI 1.6–5.7) (30).

Racial and Ethnic Differences in Stroke Risk in Diabetes

Several population studies have provided insights into the racial and ethnic differences in stroke risk (22,31,32,33). The overall findings suggest an excess stroke risk among black and Hispanic populations compared to the white population. In the Atherosclerosis Risk in Communities (ARIC) study, a black-to-white age-adjusted incidence ratio for stroke of 2.41 was observed. The Northern Manhattan Study (NOMAS) showed a Hispanic-to-white incidence ratio of 1.69. The age-adjusted incidence of first ischemic stroke per 1,000 was 0.88 in whites, 1.91 in blacks, and 1.49 in Hispanics, according to data from the NOMAS (34).

Assuming that stroke case-fatality rates are similar across the United States, studies have used stroke mortality rates to estimate geographic variations in stroke incidence. The Centers for Disease Control and Prevention showed 20% and 40% higher stroke mortality rates in the “stroke belt” (Alabama, Arkansas, Georgia, Louisiana, Mississippi, North Carolina, South Carolina, and Tennessee) and the “stroke buckle” (region along the coastal plain of North Carolina, South Carolina, and Georgia), respectively, than in the remaining states (22).

The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study is a longitudinal, population-based cohort study designed to investigate factors associated with excess stroke mortality among blacks and residents of the stroke belt region (33). Among 27,744 men and women age ≥45 years without prevalent stroke (40.4% black), 460 incident strokes were identified over 113,469 person-years of follow-up. Incident stroke was defined as first occurrence of stroke over 4.4 years of follow-up. Incidence rate ratios of stroke in the southeastern stroke belt and stroke buckle were 1.06 (95% CI 0.87–1.29) and 1.19 (95% CI 0.96–1.47), respectively. The overall age-sex-adjusted black/white incidence rate ratio was 1.51 (95% CI 1.26–1.81), but for persons age 45–54 years, the black/white incidence rate ratio was 4.02 (95% CI 1.23–13.11), and for those age ≥85 years, it was 0.86 (95% CI 0.33–2.20) (31). In a separate analysis of REGARDS data, 427 stroke events were detected over a median follow-up of 4.4 years among 25,714 black and white individuals age ≥45 years who were stroke free at baseline. Of the various vascular risk factors, hypertension and diabetes were the largest contributors to racial disparities, accounting for one-half and one-third of the joint mediating effect of all risk factors combined, respectively. In addition, blacks with stroke were twice as likely to have diabetes compared to whites (33).

FIGURE 19.6

Probability of Stroke in Women Age 55–84 Years and Free of Previous Stroke, Framingham Stroke Risk Estimator.

The GCNKSS was the first to estimate diabetes-specific incidence rates, case-fatality rates, and population attributable risks of ischemic stroke in black and white persons with diabetes within the same population. The study demonstrated a race-specific effect, with a higher risk for stroke in African Americans with diabetes compared to whites, and an age effect, with substantially increased risk for diabetic persons age <65 years compared with individuals without diabetes. The maximum risk ratios of 9.9 in those age 35–44 years for black persons with diabetes compared to nondiabetic black subjects declined gradually with age to a risk ratio of 0.8 in those age ≥85 years. The risk ratio estimates for the white diabetic versus nondiabetic populations were less dramatic but followed a similar pattern, with a risk ratio of 5.3 in persons age 45–54 years, declining to 2.3 in those age ≥85 years. These findings indicate that the risk of stroke in diabetes is somewhat higher in older white than black adults. The greatest increase in risk was seen in younger African Americans (age 35–44 years), who had a substantially higher risk than whites of the same age. The overall population attributable risk of diabetes for stroke was 5.6% in African Americans and 5.2% in whites; when combined with hypertension, the population attributable risk was 20%–21% in both races. Interestingly, the case-fatality after ischemic stroke in this study was not found to be higher in persons with diabetes. The definition of “diabetics with stroke” in the GCNKSS was based on prior diagnosis of diabetes, excluding persons who had not been diagnosed with diabetes at the time of their ischemic stroke. Therefore, the incidence rates, relative risks, and population attributable risks in this study could be underestimated (35).

In the NHANES 1971–1975, during an 8-year follow-up, a 2.5-fold higher risk of stroke was observed among persons with diabetes compared to those without; this risk was similar for black and white women and men with diabetes (36).

In the Strong Heart Study, a population-based study of 4,507 American Indian participants (mean age 59.5 years) who were free of prevalent stroke at baseline, 306 (6.8%) had a first stroke over a 12–15-year follow-up period. The hazard ratio (HR) for diabetes and impaired glucose tolerance was 2.05, where impaired glucose intolerance was defined as fasting glucose <126 mg/dL (<6.99 mmol/L) with postchallenge glucose between 140 and 199.9 mg/dL (7.77–11.09 mmol/L) (37). Overall age-adjusted incidence and case-fatality rates for stroke in American Indians were higher than those published for white or black populations in the United States.

In the Honolulu Heart Program, 8,006 Japanese American men (mean age 55 years) were followed for 12 years. Incident stroke was observed in 62.3 per 1,000 diabetic men and 32.7 per 1,000 nondiabetic men. The estimated relative risk of stroke for those with diabetes compared with those without diabetes was 2.0 (95% CI 1.4–3.0) for ischemic stroke (38).

Stroke in Young Persons With Diabetes

High-risk young men (age 35–57 years) in the Multiple Risk Factor Intervention Trial (MRFIT) were followed for 12 years. The relative risk of stroke-related mortality among participants with diabetes (N=5,163) was 2.8-fold higher compared to nondiabetic men (N=342,815). The risk was even higher among persons with diabetes who also had prevalent hyper-tension or dyslipidemia or were current smokers (39).

In 1,220 young participants (age 18–44 years) in the Baltimore-Washington Cooperative Young Stroke Study, the risk of ischemic stroke in persons with diabetes was high. The population attributable risk percent for a history of diabetes (not precisely defined as type 1 or type 2 diabetes) was high for all sex and race groups (for white men 19.0%, 95% CI 8.2%–28.5%; white women 15.8%, 95% CI 3.8%–26.3%; black men 13.2%, 95% CI 5.3%–20.4%), but highest for young black women at 22.1% (95% CI 12.5%–30.7%) (40). Population attributable risks for hypertension and smoking were also high in this cohort.

Predictors of Stroke Risk in Persons With Diabetes

Vascular risk factors may modify the risk of stroke among subjects with diabetes just as they alter stroke risk among those without diabetes (2,4,34,38). These risk factors include hypertension, smoking, hyperlipidemia, and atrial fibrillation. Hypertension is the most important of these comorbidities: the single most effective strategy to prevent stroke among persons with diabetes is to ensure optimal blood pressure control. Attention has shifted to the evaluation of diabetes-specific risk factors in modifying stroke risk among persons with diabetes (47).

Control of Stroke Risk Factors in Diabetes

The risk of stroke in persons with diabetes can be estimated based on their vascular risk factor profiles; the algorithm is similar to those used for a general population sample. In 2008, the UKPDS published a risk estimation model that can be used to predict 10-year stroke risk in persons with type 2 diabetes, based on age, presence or absence of hyperglycemia (A1c >6.3% [>45 mmol/mol] and fasting plasma insulin >9.8 μIU/mL [>58.8 pmol/L]), presence of elevated blood pressure (SBP >140 mmHg, diastolic blood pressure >80 mmHg), dyslipidemia, and history of smoking (81). The UKPDS developed a model for cardiovascular risk assessment. The UKPDS Risk Engine provides risk estimates for nonfatal and fatal stroke in individuals with type 2 diabetes. These estimates can be calculated for any given duration of type 2 diabetes based on current age, sex, ethnicity, smoking status, presence or absence of atrial fibrillation and levels of A1c, SBP, total cholesterol, and HDL cholesterol (81,82).

Treatment of Carotid and Vertebral Artery Disease

Extracranial carotid and vertebral artery disease (ECVD) is common in persons with diabetes. In asymptomatic persons with carotid bruit, duplex ultrasonography is recommended as the initial test to detect hemodynamically significant carotid stenosis (109).

2011 AHA/American Stroke Association/ACCF guidelines (109) on management of ECVD recommend diet, exercise, and antihypertensive, glucose-lowering, lipid-lowering, and antiplatelet agents as useful measures for persons with diabetes and asymptomatic ECVD. Whereas the efficacy of intensive glucose-lowering therapy to A1c <7.0% for reducing risk of stroke has not been established, aggressive management of elevated LDL cholesterol levels is recommended to lower risk of all CVD with the target LDL cholesterol ≤70 mg/dL (≤1.81 mmol/L) for persons with diabetes.

TABLE 19.3

Risk Factor Management for Primary Prevention of Stroke in Persons With Diabetes.

TABLE 19.4

Clinical Studies: Primary Stroke Prevention in Patients With Diabetes.

TABLE 19.5

Clinical Studies: Secondary Stroke Prevention in Patients With Diabetes.

Selection of carotid revascularization via carotid endarterectomy (CEA) or carotid artery stenting (CAS) for asymptomatic and symptomatic carotid artery disease should be guided by the degree of stenosis, assessment of comorbid conditions, life expectancy, and individual surgical/procedural risk and should include a thorough discussion of the risks and benefits of the procedure and medical management with an understanding of patient preferences.

Asymptomatic carotid disease with <70% stenosis is uniformly treated with aggressive medical management and close surveillance with carotid ultrasound for disease progression. In selected patients with asymptomatic carotid disease with ≥70% stenosis and low perioperative risk for stroke, myocardial infarction, or death (<6%), CEA is readily offered, but mostly to patients with progression of carotid stenosis from mild-moderate to severe despite aggressive medical management. In the past decade, this practice is becoming more controversial, and carotid revascularization in patients with asymptomatic high grade stenosis (>70%) is center-based and personalized based on response to aggressive medical management.

Persons who experience nondisabling ischemic stroke or TIA due to carotid artery disease are defined as symptomatic patients. Carotid revascularization is generally considered beneficial for symptomatic carotid disease with ≥70% artery stenosis as detected by carotid ultrasound or >50% as detected by catheter angiography. If perioperative risk for stroke, cardiac complications, and death is low (<6%), these patients should undergo CEA within 2–4 weeks of diagnosis, as most events occur early and the relative benefit from surgery continues to drop after this time. However, if the perioperative risk is high (≥6%), these patients should be considered for CAS.

Medical management and antiplatelet therapy are recommended before and after carotid recanalization. Noninvasive imaging at 1 month, 6 months, and annually to evaluate for restenosis is recommended for all patients who undergo CEA or CAS. Once patients are no longer candidates for revascularization, noninvasive surveillance of carotid artery can be terminated.

Disease Course and Prognosis After Stroke in Persons With Diabetes

Diabetes is a common risk factor for incident stroke, as well as an independent risk factor for stroke recurrence. Diabetes adversely impacts stroke severity, survival (case-fatality) after stroke, cognitive function, and disability after stroke.

The Get With the Guidelines-Stroke program found a significant difference in stroke-related outcomes between persons with and without diabetes. Patients with diabetes had worse outcomes; they were less able to ambulate at discharge and were more likely to be discharged to a skilled nursing facility or an inpatient acute rehabilitation. The length of hospital stay for persons with diabetes was longer compared to patients without diabetes. The adjusted odds of in-hospital mortality were also elevated in persons with diabetes (OR 1.12, 95% CI 1.08–1.15). In a study of health-related quality of life, diabetes was found to be an independent risk factor for worse quality of life at 1-year post-stroke (110). Using data from the Vitamin Intervention in Stroke Prevention Study, Newman et al. evaluated >3,000 subjects over 1 year post-stroke; a sole diagnosis of diabetes was associated with worse outcomes on both the Mini Mental Status Examination (a measure of cognitive status) and modified Rankin Score (a measure of disability), suggesting that diabetes impacts cognitive and motor recovery in stroke survivors (111).

Conclusion

Diabetes is an independent risk factor for ischemic stroke. Persons with diabetes are equally at risk of having a small or large vessel ischemic stroke, and risks are higher among American Indian, black, and Hispanic persons compared to whites. Persons with diabetes who suffer a stroke have a higher risk of recurrent stroke and of mortality and morbidity. Stroke risk among persons with diabetes can be reduced through comprehensive control of cardiovascular risk factors and carefully monitored lifestyle interventions. Health care providers are encouraged to be vigilant in monitoring and treating elevated blood pressure and blood lipid levels. In addition, careful surveillance for asymptomatic vascular disease, such as carotid artery disease, coronary disease, and atrial fibrillation, and all well-established risk factors for stroke should be addressed promptly. All women age >60 years and men age >50 years with diabetes and an additional vascular risk factor should be offered antiplatelet therapy. Persons with diabetes who experience a stroke could benefit from targeted attention to ensure appropriate medical care and intense rehabilitation efforts to improve their outcomes following stroke.

Additional studies are needed to evaluate stroke risk in prediabetic states, to identify a biomarker profile that may predict stroke in persons with diabetes, and to examine new preventive and therapeutic interventions in these individuals.

List of Abbreviations

A1c

glycosylated hemoglobin

ACCF

American College of Cardiology Foundation

ACEI

angiotensin-converting enzyme inhibitor

ADA

American Diabetes Association

ADVANCE

Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation trial

AGE

advanced glycation endproduct

AHA

American Heart Association

ARB

angiotensin receptor blocker

ARIC

Atherosclerosis Risk in Communities study

BMI

body mass index

CARDS

Collaborative Atorvastatin Diabetes Study

CAS

carotid artery stenting

CBI

covert brain infarct

CEA

carotid endarterectomy

CI

confidence interval

CRP

C-reactive protein

CT

computed tomography

CVD

cardiovascular disease

DAN

diabetic autonomic neuropathy

DCCT

Diabetes Control and Complications Trial

DWI

diffuse weighted imaging

ECVD

extracranial carotid and vertebral artery disease

eGFR

estimated glomerular filtration rate

FHS

Framingham Heart Study

GCNKSS

Greater Cincinnati/Northern Kentucky Stroke Study

HDL

high-density lipoprotein

HOMA-IR

homeostasis model assessment of insulin resistance

HR

hazard ratio

hsCRP

high sensitivity C-reactive protein

IGF-1

insulin-like growth factor 1

IGFBP-1

IGF binding protein 1

IRIS

Insulin Resistance Intervention after Stroke trial

JNC 8

Eighth Joint National Committee

LDL

low-density lipoprotein

MRI

magnetic resonance imaging

NHANES

National Health and Nutrition Examination Survey

NHIS

National Health Interview Survey

NHS

Nurses’ Health Study

NO

nitric oxide

NOMAS

Northern Manhattan Study

OR

odds ratio

OSA

obstructive sleep apnea

RAGE

receptor for advanced glycation endproduct

REGARDS

Reasons for Geographic and Racial Differences in Stroke study

ROS

reactive oxygen species

RR

relative risk

SBP

systolic blood pressure

SPARCL

Stroke Prevention by Aggressive Reduction in Cholesterol Levels trial

sRAGE

soluble RAGE

TIA

transient ischemic attack

UAC

urine albumin concentration

UACR

urine albumin-to-creatinine ratio

UKPDS

United Kingdom Prospective Diabetes Study

WMH

white matter hyperintensities

References

1.

Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Judd SE, Kissela BM, Lackland DT, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Matchar DB, McGuire DK, Mohler ER, 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Willey JZ, Woo D, Yeh RW, Turner MB; American Heart Association Statistics Committee and Stroke Statistics Subcommittee: Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation 131:e29–e322, 2015 [PubMed: 25520374]

2.

Caplan LR: Acute stroke: seeing the full picture. Hosp Pract 35:65–71, 2000 [PubMed: 10884819]

3.

Caplan LR: Intracerebral haemorrhage. Lancet 339:656–658, 1992 [PubMed: 1347346]

4.

Ay H, Benner T, Arsava EM, Furie KL, Singhal AB, Jensen MB, Ayata C, Towfighi A, Smith EE, Chong JY, Koroshetz WJ, Sorensen AG: A computerized algorithm for etiologic classification of ischemic stroke: the Causative Classification of Stroke System. Stroke 38:2979–2984, 2007 [PubMed: 17901381]

5.

Furie KL, Kasner SE, Adams RJ, Albers GW, Bush RL, Fagan SC, Halperin JL, Johnston SC, Katzan I, Kernan WN, Mitchell PH, Ovbiagele B, Palesch YY, Sacco RL, Schwamm LH, Wassertheil-Smoller S, Turan TN, Wentworth D; American Heart Association Stroke Council; Council on Cardiovascular Nursing, Council on Clinical Cardiology; and Interdisciplinary Council on Quality of Care and Outcomes Research: Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 42:227–276, 2011 [PubMed: 20966421]

6.

Easton JD, Saver JL, Albers GW, Alberts MJ, Chaturvedi S, Feldmann E, Hatsukami TS, Higashida RT, Johnston SC, Kidwell CS, Lutsep HL, Miller E, Sacco RL; American Heart Association; American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; Interdisciplinary Council on Peripheral Vascular Disease: Definition and evaluation of transient ischemic attack: a scientific statement for health-care professionals from the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease. The American Academy of Neurology affirms the value of this statement as an educational tool for neurologists. Stroke 40:2276–2293, 2009 [PubMed: 19423857]

7.

Debette S, Markus HS: The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 341:c3666, 2010 [PMC free article: PMC2910261] [PubMed: 20660506]

8.

Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM: Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 348:1215–1222, 2003 [PubMed: 12660385]

9.

Ariesen MJ, Claus SP, Rinkel GJ, Algra A: Risk factors for intracerebral hemorrhage in the general population: a systematic review. Stroke 34:2060–2065, 2003 [PubMed: 12843354]

10.

Longstreth WT, Jr.: Brain vascular disease overt and covert. Stroke 36:2062–2063, 2005 [PubMed: 16192459]

11.

Beckman JA, Creager MA, Libby P: Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 287:2570–2581, 2002 [PubMed: 12020339]

12.

Lee M, Saver JL, Chang KH, Liao HW, Chang SC, Ovbiagele B: Impact of microalbuminuria on incident stroke: a meta-analysis. Stroke 41:2625–2631, 2010 [PubMed: 20930164]

13.

Pikula A, Beiser AS, DeCarli C, Himali JJ, Debette S, Au R, Selhub J, Toffler GH, Wang TJ, Meigs JB, Kelly-Hayes M, Kase CS, Wolf PA, Vasan RS, Seshadri S: Multiple biomarkers and risk of clinical and subclinical vascular brain injury: the Framingham Offspring Study. Circulation 125:2100–2107, 2012 [PMC free article: PMC3427730] [PubMed: 22456473]

14.

Meigs JB, D’Agostino RB, Sr., Nathan DM, Rifai N, Wilson PW; Framingham Offspring Study: Longitudinal association of glycemia and microalbuminuria: the Framingham Offspring Study. Diabetes Care 25:977–983, 2002 [PubMed: 12032102]

15.

Nelson RG, Bennett PH, Beck GJ, Tan M, Knowler WC, Mitch WE, Hirschman GH, Myers BD: Development and progression of renal disease in Pima Indians with non-insulin-dependent diabetes mellitus. Diabetic Renal Disease Study Group. N Engl J Med 335:1636–1642, 1996 [PubMed: 8929360]

16.

Gillett M, Davis WA, Jackson D, Bruce DG, Davis TM; Fremantle Diabetes Study: Prospective evaluation of carotid bruit as a predictor of first stroke in type 2 diabetes: the Fremantle Diabetes Study. Stroke 34:2145–2151, 2003 [PubMed: 12907819]

17.

Lee M, Saver JL, Chang KH, Liao HW, Chang SC, Ovbiagele B: Low glomerular filtration rate and risk of stroke: meta-analysis. BMJ 341:c4249, 2010 [PMC free article: PMC2948650] [PubMed: 20884696]

18.

Cohen JA, Estacio RO, Lundgren RA, Esler AL, Schrier RW: Diabetic autonomic neuropathy is associated with an increased incidence of strokes. Auton Neurosci 108:73–78, 2003 [PubMed: 14614967]

19.

Cellek S, Anderson PN, Foxwell NA: Nitrergic neurodegeneration in cerebral arteries of streptozotocin-induced diabetic rats: a new insight into diabetic stroke. Diabetes 54:212–219, 2005 [PubMed: 15616031]

20.

Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman MD, Judd SE, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Mackey RH, Magid DJ, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER, 3rd, Moy CS, Mussolino ME, Neumar RW, Nichol G, Pandey DK, Paynter NP, Reeves MJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Wong ND, Woo D, Turner MB; American Heart Association Statistics Committee and Stroke Statistics Subcommittee: Heart disease and stroke statistics—2014 update: a report from the American Heart Association. Circulation 129:e28–e292, 2014 [PMC free article: PMC5408159] [PubMed: 24352519]

21.

Seshadri S, Beiser A, Kelly-Hayes M, Kase CS, Au R, Kannel WB, Wolf PA: The lifetime risk of stroke: estimates from the Framingham Study. Stroke 37:345–350, 2006 [PubMed: 16397184]

22.

Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Makuc DM, Marcus GM, Marelli A, Matchar DB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter NP, Soliman EZ, Sorlie PD, Sotoodehnia N, Turan TN, Virani SS, Wong ND, Woo D, Turner MB; American Heart Association Statistics Committee and Stroke Statistics Subcommittee: Heart disease and stroke statistics—2012 update: a report from the American Heart Association. Circulation 125:e2–e220, 2012 [PMC free article: PMC4440543] [PubMed: 22179539]

23.

Gregg EW, Cheng YJ, Saydah S, Cowie C, Garfield S, Geiss L, Barker L: Trends in death rates among U.S. adults with and without diabetes between 1997 and 2006: findings from the National Health Interview Survey. Diabetes Care 35:1252–1257, 2012 [PMC free article: PMC3357247] [PubMed: 22619288]

24.

Secrest AM, Prince CT, Costacou T, Miller RG, Orchard TJ: Predictors of and survival after incident stroke in type 1 diabetes. Diab Vasc Dis Res 10:3–10, 2013 [PMC free article: PMC3635676] [PubMed: 22535586]

25.

Roy MS, Peng B, Roy A: Risk factors for coronary disease and stroke in previously hospitalized African-Americans with type 1 diabetes: a 6-year follow-up. Diabet Med 24:1361–1368, 2007 [PubMed: 17976202]

26.

Janghorbani M, Hu FB, Willett WC, Manson JE, Logroscino G, Rexrode KM: Prospective study of type 1 and type 2 diabetes and risk of stroke subtypes: the Nurses’ Health Study. Diabetes Care 30:1730–1735, 2007 [PubMed: 17389335]

27.

Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, Ford E, Furie K, Go A, Greenlund K, Haase N, Hailpern S, Ho M, Howard V, Kissela B, Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott M, Meigs J, Mozaffarian D, Nichol G, O’Donnell C, Roger V, Rosamond W, Sacco R, Sorlie P, Stafford R, Steinberger J, Thom T, Wasserthiel-Smoller S, Wong N, Wylie-Rosett J, Hong Y; American Heart Association Statistics Committee and Stroke Statistics Subcommittee: Heart disease and stroke statistics—2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 119:e21–e181, 2009 [PubMed: 19075105]

28.

Wolf PA, D’Agostino RB, Belanger AJ, Kannel WB: Probability of stroke: a risk profile from the Framingham Study. Stroke 22:312–318, 1991 [PubMed: 2003301]

29.

Barrett-Connor E, Khaw KT: Diabetes mellitus: an independent risk factor for stroke? Am J Epidemiol 128:116–123, 1988 [PubMed: 3381820]

30.

Manson JE, Colditz GA, Stampfer MJ, Willett WC, Krolewski AS, Rosner B, Arky RA, Speizer FE, Hennekens CH: A prospective study of maturity-onset diabetes mellitus and risk of coronary heart disease and stroke in women. Arch Intern Med 151:1141–1147, 1991 [PubMed: 2043016]

31.

Howard VJ, Kleindorfer DO, Judd SE, McClure LA, Safford MM, Rhodes JD, Cushman M, Moy CS, Soliman EZ, Kissela BM, Howard G: Disparities in stroke incidence contributing to disparities in stroke mortality. Ann Neurol 69:619–627, 2011 [PMC free article: PMC3595534] [PubMed: 21416498]

32.

Howard G, Labarthe DR, Hu J, Yoon S, Howard VJ: Regional differences in African Americans’ high risk for stroke: the remarkable burden of stroke for Southern African Americans. Ann Epidemiol 17:689–696, 2007 [PMC free article: PMC1995237] [PubMed: 17719482]

33.

Howard G, Cushman M, Kissela BM, Kleindorfer DO, McClure LA, Safford MM, Rhodes JD, Soliman EZ, Moy CS, Judd SE, Howard VJ; REasons for Geographic And Racial Differences in Stroke (REGARDS) Investigators: Traditional risk factors as the underlying cause of racial disparities in stroke: lessons from the half-full (empty?) glass. Stroke 42:3369–3375, 2011 [PMC free article: PMC3226886] [PubMed: 21960581]

34.

White H, Boden-Albala B, Wang C, Elkind MS, Rundek T, Wright CB, Sacco RL: Ischemic stroke subtype incidence among whites, blacks, and Hispanics: the Northern Manhattan Study. Circulation 111:1327–1331, 2005 [PubMed: 15769776]

35.

Kissela BM, Khoury J, Kleindorfer D, Woo D, Schneider A, Alwell K, Miller R, Ewing I, Moomaw CJ, Szaflarski JP, Gebel J, Shukla R, Broderick JP: Epidemiology of ischemic stroke in patients with diabetes: the Greater Cincinnati/Northern Kentucky Stroke Study. Diabetes Care 28:355–359, 2005 [PubMed: 15677792]

36.

Kittner SJ, White LR, Losonczy KG, Wolf PA, Hebel JR: Black-white differences in stroke incidence in a national sample. The contribution of hypertension and diabetes mellitus. JAMA 264:1267–1270, 1990 [PubMed: 2388378]

37.

Zhang Y, Galloway JM, Welty TK, Wiebers DO, Whisnant JP, Devereux RB, Kizer JR, Howard BV, Cowan LD, Yeh J, Howard WJ, Wang W, Best L, Lee ET: Incidence and risk factors for stroke in American Indians: the Strong Heart Study. Circulation 118:1577–1584, 2008 [PMC free article: PMC2754380] [PubMed: 18809797]

38.

Abbott RD, Donahue RP, MacMahon SW, Reed DM, Yano K: Diabetes and the risk of stroke. The Honolulu Heart Program. JAMA 257:949–952, 1987 [PubMed: 3806877]

39.

Stamler J, Vaccaro O, Neaton JD, Wentworth D: Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 16:434–444, 1993 [PubMed: 8432214]

40.

Rohr J, Kittner S, Feeser B, Hebel JR, Whyte MG, Weinstein A, Kanarak N, Buchholz D, Earley C, Johnson C, Macko R, Price T, Sloan M, Stern B, Wityk R, Wozniak M, Sherwin R: Traditional risk factors and ischemic stroke in young adults: the Baltimore-Washington Cooperative Young Stroke Study. Arch Neurol 53:603–607, 1996 [PubMed: 8929167]

41.

Labovitz DL, Boden-Albala B, Hauser WA, Sacco RL: Lacunar infarct or deep intracerebral hemorrhage: who gets which? The Northern Manhattan Study. Neurology 68:606–608, 2007 [PubMed: 17310033]

42.

Longstreth WT, Jr., Bernick C, Manolio TA, Bryan N, Jungreis CA, Price TR: Lacunar infarcts defined by magnetic resonance imaging of 3660 elderly people: the Cardiovascular Health Study. Arch Neurol 55:1217–1225, 1998 [PubMed: 9740116]

43.

Folsom AR, Eckfeldt JH, Weitzman S, Ma J, Chambless LE, Barnes RW, Cram KB, Hutchinson RG: Relation of carotid artery wall thickness to diabetes mellitus, fasting glucose and insulin, body size, and physical activity. Atherosclerosis Risk in Communities (ARIC) Study Investigators. Stroke 25:66–73, 1994 [PubMed: 8266385]

44.

Wagenknecht LE, D’Agostino R, Jr., Savage PJ, O’Leary DH, Saad MF, Haffner SM: Duration of diabetes and carotid wall thickness. The Insulin Resistance Atherosclerosis Study (IRAS). Stroke 28:999–1005, 1997 [PubMed: 9158641]

45.

Arenillas JF, Molina CA, Chacon P, Rovira A, Montaner J, Coscojuela P, Sanchez E, Quintana M, Alvarez-Sabin J: High lipoprotein (a), diabetes, and the extent of symptomatic intracranial atherosclerosis. Neurology 63:27–32, 2004 [PubMed: 15249606]

46.

Abbott RD, Brand FN, Kannel WB: Epidemiology of some peripheral arterial findings in diabetic men and women: experiences from the Framingham Study. Am J Med 88:376–381, 1990 [PubMed: 2327425]

47.

Hitman GA, Colhoun H, Newman C, Szarek M, Betteridge DJ, Durrington PN, Fuller J, Livingstone S, Neil HA; CARDS Investigators: Stroke prediction and stroke prevention with atorvastatin in the Collaborative Atorvastatin Diabetes Study (CARDS). Diabet Med 24:1313–1321, 2007 [PubMed: 17894827]

48.

Boden-Albala B, Cammack S, Chong J, Wang C, Wright C, Rundek T, Elkind MS, Paik MC, Sacco RL: Diabetes, fasting glucose levels, and risk of ischemic stroke and vascular events: findings from the Northern Manhattan Study (NOMAS). Diabetes Care 31:1132–1137, 2008 [PubMed: 18339972]

49.

Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC: Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke 32:2426–2432, 2001 [PubMed: 11588337]

50.

Yong M, Kaste M: Dynamic of hyperglycemia as a predictor of stroke outcome in the ECASS-II trial. Stroke 39:2749–2755, 2008 [PubMed: 18703813]

51.

Bruno A, Kent TA, Coull BM, Shankar RR, Saha C, Becker KJ, Kissela BM, Williams LS: Treatment of Hyperglycemia in Ischemic Stroke (THIS): a randomized pilot trial. Stroke 39:384–389, 2008 [PubMed: 18096840]

52.

Eckel RH, Grundy SM, Zimmet PZ: The metabolic syndrome. Lancet 365:1415–1428, 2005 [PubMed: 15836891]

53.

Bravata DM, Wells CK, Kernan WN, Concato J, Brass LM, Gulanski BI: Association between impaired insulin sensitivity and stroke. Neuroepidemiology 25:69–74, 2005 [PubMed: 15947493]

54.

Rundek T, Gardener H, Xu Q, Goldberg RB, Wright CB, Boden-Albala B, Disla N, Paik MC, Elkind MS, Sacco RL: Insulin resistance and risk of ischemic stroke among nondiabetic individuals from the Northern Manhattan Study. Arch Neurol 67:1195–1200, 2010 [PMC free article: PMC2954671] [PubMed: 20937946]

55.

Air EL, Kissela BM: Diabetes, the metabolic syndrome, and ischemic stroke: epidemiology and possible mechanisms. Diabetes Care 30:3131–3140, 2007 [PubMed: 17848611]

56.

Eguchi K, Boden-Albala B, Jin Z, Di Tullio MR, Rundek T, Rodriguez CJ, Homma S, Sacco RL: Usefulness of fasting blood glucose to predict vascular outcomes among individuals without diabetes mellitus (from the Northern Manhattan Study). Am J Cardiol 100:1404–1409, 2007 [PubMed: 17950798]

57.

Ballantyne CM, Hoogeveen RC, McNeill AM, Heiss G, Schmidt MI, Duncan BB, Pankow JS: Metabolic syndrome risk for cardiovascular disease and diabetes in the ARIC study. Int J Obes (Lond) 32(Suppl 2):S21–S24, 2008 [PMC free article: PMC4944387] [PubMed: 18469836]

58.

Boden-Albala B, Sacco RL, Lee HS, Grahame-Clarke C, Rundek T, Elkind MV, Wright C, Giardina EG, DiTullio MR, Homma S, Paik MC: Metabolic syndrome and ischemic stroke risk: Northern Manhattan Study. Stroke 39:30–35, 2008 [PMC free article: PMC2677015] [PubMed: 18063821]

59.

Rundek T, White H, Boden-Albala B, Jin Z, Elkind MS, Sacco RL: The metabolic syndrome and subclinical carotid atherosclerosis: the Northern Manhattan Study. J Cardiometab Syndr 2:24–29, 2007 [PubMed: 17684455]

60.

Cull CA, Jensen CC, Retnakaran R, Holman RR: Impact of the metabolic syndrome on macrovascular and micro-vascular outcomes in type 2 diabetes mellitus: United Kingdom Prospective Diabetes Study 78. Circulation 116:2119–2126, 2007 [PubMed: 17967769]

61.

Najarian RM, Sullivan LM, Kannel WB, Wilson PW, D’Agostino RB, Wolf PA: Metabolic syndrome compared with type 2 diabetes mellitus as a risk factor for stroke: the Framingham Offspring Study. Arch Intern Med 166:106–111, 2006 [PubMed: 16401818]

62.

Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V: Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 353:2034–2041, 2005 [PubMed: 16282178]

63.

Einhorn D, Stewart DA, Erman MK, Gordon N, Philis-Tsimikas A, Casal E: Prevalence of sleep apnea in a population of adults with type 2 diabetes mellitus. Endocr Pract 13:355–362, 2007 [PubMed: 17669711]

64.

Foster GD, Sanders MH, Millman R, Zammit G, Borradaile KE, Newman AB, Wadden TA, Kelley D, Wing RR, Sunyer FX, Darcey V, Kuna ST; Sleep AHEAD Research Group: Obstructive sleep apnea among obese patients with type 2 diabetes. Diabetes Care 32:1017–1019, 2009 [PMC free article: PMC2681024] [PubMed: 19279303]

65.

Bassetti C, Aldrich MS: Sleep apnea in acute cerebrovascular diseases: final report on 128 patients. Sleep 22:217–223, 1999 [PubMed: 10201066]

66.

Rost NS, Wolf PA, Kase CS, Kelly-Hayes M, Silbershatz H, Massaro JM, D’Agostino RB, Franzblau C, Wilson PW: Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham Study. Stroke 32:2575–2579, 2001 [PubMed: 11692019]

67.

Ridker PM: Cardiology patient page. C-reactive protein: a simple test to help predict risk of heart attack and stroke. Circulation 108:e81–e85, 2003 [PubMed: 14504253]

68.

Monnier VM, Sell DR, Genuth S: Glycation products as markers and predictors of the progression of diabetic complications. Ann N Y Acad Sci 1043:567–581, 2005 [PubMed: 16037280]

69.

Schmidt AM, Yan SD, Yan SF, Stern DM: The biology of the receptor for advanced glycation end products and its ligands. Biochim Biophys Acta 1498:99–111, 2000 [PubMed: 11108954]

70.

Colhoun HM, Betteridge DJ, Durrington P, Hitman G, Neil A, Livingstone S, Charlton-Menys V, Bao W, Demicco DA, Preston GM, Deshmukh H, Tan K, Fuller JH: Total soluble and endogenous secretory receptor for advanced glycation end products as predictive biomarkers of coronary heart disease risk in patients with type 2 diabetes: an analysis from the CARDS trial. Diabetes 60:2379–2385, 2011 [PMC free article: PMC3161327] [PubMed: 21771973]

71.

Kim JK, Park S, Lee MJ, Song YR, Han SH, Kim SG, Kang SW, Choi KH, Kim HJ, Yoo TH: Plasma levels of soluble receptor for advanced glycation end products (sRAGE) and proinflammatory ligand for RAGE (EN-RAGE) are associated with carotid atherosclerosis in patients with peritoneal dialysis. Atherosclerosis 220:208–214, 2012 [PubMed: 21906738]

72.

Selvin E, Halushka MK, Rawlings AM, Hoogeveen RC, Ballantyne CM, Coresh J, Astor BC: sRAGE and risk of diabetes, cardiovascular disease, and death. Diabetes 62:2116–2121, 2013 [PMC free article: PMC3661610] [PubMed: 23396398]

73.

Calles-Escandon J, Garcia-Rubi E, Mirza S, Mortensen A: Type 2 diabetes: one disease, multiple cardiovascular risk factors. Coron Artery Dis 10:23–30, 1999 [PubMed: 10196684]

74.

Carr ME: Diabetes mellitus: a hypercoagulable state. J Diabetes Complications 15:44–54, 2001 [PubMed: 11259926]

75.

Friedrich N, Alte D, Volzke H, Spilcke-Liss E, Ludemann J, Lerch MM, Kohlmann T, Nauck M, Wallaschofski H: Reference ranges of serum IGF-1 and IGFBP-3 levels in a general adult population: results of the Study of Health in Pomerania (SHIP). Growth Horm IGF Res 18:228–237, 2008 [PubMed: 17997337]

76.

van Rijn MJ, Slooter AJ, Bos MJ, Catarino CF, Koudstaal PJ, Hofman A, Breteler MM, van Duijn CM: Insulin-like growth factor I promoter polymorphism, risk of stroke, and survival after stroke: the Rotterdam study. J Neurol Neurosurg Psychiatry 77:24–27, 2006 [PMC free article: PMC2117398] [PubMed: 16361587]

77.

Kaplan RC, McGinn AP, Pollak MN, Kuller LH, Strickler HD, Rohan TE, Cappola AR, Xue X, Psaty BM: Association of total insulin-like growth factor-I, insulin-like growth factor binding protein-1 (IGFBP-1), and IGFBP-3 levels with incident coronary events and ischemic stroke. J Clin Endocrinol Metab 92:1319–1325, 2007 [PubMed: 17264182]

78.

Johnsen SP, Hundborg HH, Sorensen HT, Orskov H, Tjonneland A, Overvad K, Jorgensen JO: Insulin-like growth factor (IGF) I, -II, and IGF binding protein-3 and risk of ischemic stroke. J Clin Endocrinol Metab 90:5937–5941, 2005 [PubMed: 16131586]

79.

Sandhu MS, Heald AH, Gibson JM, Cruickshank JK, Dunger DB, Wareham NJ: Circulating concentrations of insulin-like growth factor-I and development of glucose intolerance: a prospective observational study. Lancet 359:1740–1745, 2002 [PubMed: 12049864]

80.

Heald AH, Siddals KW, Fraser W, Taylor W, Kaushal K, Morris J, Young RJ, White A, Gibson JM: Low circulating levels of insulin-like growth factor binding protein-1 (IGFBP-1) are closely associated with the presence of macrovascular disease and hypertension in type 2 diabetes. Diabetes 51:2629–2636, 2002 [PubMed: 12145180]

81.

Adler AI: UKPDS-modelling of cardiovascular risk assessment and lifetime simulation of outcomes. Diabet Med 25(Suppl 2):41–46, 2008 [PubMed: 18717978]

82.

Kothari V, Stevens RJ, Adler AI, Stratton IM, Manley SE, Neil HA, Holman RR: UKPDS 60: risk of stroke in type 2 diabetes estimated by the UK Prospective Diabetes Study risk engine. Stroke 33:1776–1781, 2002 [PubMed: 12105351]

83.

Goldstein LB, Bushnell CD, Adams RJ, Appel LJ, Braun LT, Chaturvedi S, Creager MA, Culebras A, Eckel RH, Hart RG, Hinchey JA, Howard VJ, Jauch EC, Levine SR, Meschia JF, Moore WS, Nixon JV, Pearson TA; American Heart Association Stroke Council; Council on Cardiovascular Nursing; Council on Epidemiology and Prevention; Council for High Blood Pressure Research; Council on Peripheral Vascular Disease; and Interdisciplinary Council on Quality of Care and Outcomes Research: Guidelines for the primary prevention of stroke: a guideline for health-care professionals from the American Heart Association/American Stroke Association. Stroke 42:517–584, 2011 [PubMed: 21127304]

84.

Curb JD, Pressel SL, Cutler JA, Savage PJ, Applegate WB, Black H, Camel G, Davis BR, Frost PH, Gonzalez N, Guthrie G, Oberman A, Rutan GH, Stamler J: Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. Systolic Hypertension in the Elderly Program Cooperative Research Group. JAMA 276:1886–1892, 1996 [PubMed: 8968014]

85.

Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, Wright AD, Turner RC, Holman RR: Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ 321:412–419, 2000 [PMC free article: PMC27455] [PubMed: 10938049]

86.

Bangalore S, Kumar S, Lobach I, Messerli FH: Blood pressure targets in subjects with type 2 diabetes mellitus/impaired fasting glucose: observations from traditional and Bayesian random-effects meta-analyses of randomized trials. Circulation 123:2799–2810, 2011 [PubMed: 21632497]

87.

James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, Smith SC, Jr., Svetkey LP, Taler SJ, Townsend RR, Wright JT, Jr., Narva AS, Ortiz E: 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 311:507–520, 2014 [PubMed: 24352797]

88.

American Diabetes Association: 8. Cardiovascular disease and risk management. Diabetes Care 39(Suppl 1):S60–S71, 2016 [PubMed: 26696684]

89.

Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet 355:253–259, 2000 [PubMed: 10675071]

90.

Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H; LIFE Study Group: Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 359:995–1003, 2002 [PubMed: 11937178]

91.

Patel A; ADVANCE Collaborative Group, MacMahon S, Chalmers J, Neal B, Woodward M, Billot L, Harrap S, Poulter N, Marre M, Cooper M, Glasziou P, Grobbee DE, Hamet P, Heller S, Liu LS, Mancia G, Mogensen CE, Pan CY, Rodgers A, Williams B: Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 370:829–840, 2007 [PubMed: 17765963]

92.

Amarenco P, Goldstein LB, Szarek M, Sillesen H, Rudolph AE, Callahan A, 3rd, Hennerici M, Simunovic L, Zivin JA, Welch KM; SPARCL Investigators: Effects of intense low-density lipoprotein cholesterol reduction in patients with stroke or transient ischemic attack: the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Stroke 38:3198–3204, 2007 [PubMed: 17962589]

93.

Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V, Fuller JH; CARDS investigators: Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 364:685–696, 2004 [PubMed: 15325833]

94.

Cholesterol Treatment Trialists’ (CTT) Collaborators; Kearney PM, Blackwell L, Collins R, Keech A, Simes J, Peto R, Armitage J, Baigent C: Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 371:117–125, 2008 [PubMed: 18191683]

95.

Callahan A, Amarenco P, Goldstein LB, Sillesen H, Messig M, Samsa GP, Altafullah I, Ledbetter LY, MacLeod MJ, Scott R, Hennerici M, Zivin JA, Welch KM; SPARCL Investigators: Risk of stroke and cardiovascular events after ischemic stroke or transient ischemic attack in patients with type 2 diabetes or metabolic syndrome: secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Arch Neurol 68:1245–1251, 2011 [PubMed: 21670382]

96.

Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC, Jr., Watson K, Wilson PW; American College of Cardiology/American Heart Association Task Force on Practice Guidelines: 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 63:2889–2934, 2014 [PubMed: 24239923]

97.

Meschia JF, Bushnell C, Boden-Albala B, Braun LT, Bravata DM, Chaturvedi S, Creager MA, Eckel RH, Elkind MS, Fornage M, Goldstein LB, Greenberg SM, Horvath SE, Iadecola C, Jauch EC, Moore WS, Wilson JA; American Heart Association Stroke Council; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Functional Genomics and Translational Biology; Council on Hypertension: Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 45:3754–3832, 2014 [PMC free article: PMC5020564] [PubMed: 25355838]

98.

Action to Control Cardiovascular Risk in Diabetes Study Group; Gerstein HC, Miller ME, Byington RP, Goff DC, Jr., Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH, Jr., Probstfield JL, Simons-Morton DG, Friedewald WT: Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 358:2545–2559, 2008 [PMC free article: PMC4551392] [PubMed: 18539917]

99.

ADVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F: Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 358:2560–2572, 2008 [PubMed: 18539916]

100.

Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG, Huang GD; VADT Investigators: Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 360:129–139, 2009 [PubMed: 19092145]

101.

Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352:837–853, 1998 [PubMed: 9742976]

102.

Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352:854–865, 1998 [PubMed: 9742977]

103.

Effect of intensive diabetes management on macrovascular events and risk factors in the Diabetes Control and Complications Trial. Am J Cardiol 75:894–903, 1995 [PubMed: 7732997]

104.

Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, Raskin P, Zinman B; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group: Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 353:2643–2653, 2005 [PMC free article: PMC2637991] [PubMed: 16371630]

105.

Wilcox R, Bousser MG, Betteridge DJ, Schernthaner G, Pirags V, Kupfer S, Dormandy J; PROactive Investigators: Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: results from PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04). Stroke 38:865–873, 2007 [PubMed: 17290029]

106.

Wilcox R, Kupfer S, Erdmann E; PROactive Study investigators: Effects of pioglitazone on major adverse cardiovascular events in high-risk patients with type 2 diabetes: results from PROspective pioglitAzone Clinical Trial In macro Vascular Events (PROactive 10). Am Heart J 155:712–717, 2008 [PubMed: 18371481]

107.

Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, Guarino PD, Lovejoy AM, Peduzzi PN, Conwit R, Brass LM, Schwartz GG, Adams HP, Jr., Berger L, Carolei A, Clark W, Coull B, Ford GA, Kleindorfer D, O’Leary JR, Parsons MW, Ringleb P, Sen S, Spence JD, Tanne D, Wang D, Winder TR; IRIS Trial Investigators: Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 374:1321–1331, 2016 [PMC free article: PMC4887756] [PubMed: 26886418]

108.

Antithrombotic Trialists’ Collaboration: Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 324:71–86, 2002 [PMC free article: PMC64503] [PubMed: 11786451]

109.

Brott TG, Halperin JL, Abbara S, Bacharach JM, Barr JD, Bush RL, Cates CU, Creager MA, Fowler SB, Friday G, Hertzberg VS, McIff EB, Moore WS, Panagos PD, Riles TS, Rosenwasser RH, Taylor AJ; American College of Cardiology; American Stroke Association; American Association of Neurological Surgeons; American College of Radiology; American College of Radiology; Society of NeuroInterventional Surgery; Society for Vascular Medicine; Society for Vascular Surgery: 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery. Circulation 124:e54–e130, 2011 [PubMed: 21282504]

110.

Reeves MJ, Vaidya RS, Fonarow GC, Liang L, Smith EE, Matulonis R, Olson DM, Schwamm LH; Get With The Guidelines Steering Committee and Hospitals: Quality of care and outcomes in patients with diabetes hospitalized with ischemic stroke: findings from Get With the Guidelines-Stroke. Stroke 41:e409–e417, 2010 [PubMed: 20224058]

111.

Newman GC, Bang H, Hussain SI, Toole JF: Association of diabetes, homocysteine, and HDL with cognition and disability after stroke. Neurology 69:2054–2062, 2007 [PubMed: 18040011]

CONVERSIONS

Conversions for A1c, glucose, insulin, LDL cholesterol, and triglyceride values are provided in Diabetes in America Appendix 1 Conversions.

DUALITY OF INTEREST

Drs. Pikula, Howard, and Seshadri reported no conflicts of interest.

ACKNOWLEDGMENTS/FUNDING The authors appreciate the editorial assistance of Rachel Schaperow.